9-95508271-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000264.5(PTCH1):c.91G>A(p.Gly31Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,570,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G31E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.131

Variant links:

Genes affected

PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]

PTCH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP2

Missense variant where missense usually causes diseases, PTCH1

BP4

Computational evidence support a benign effect (MetaRNN=0.15717536).

BP6

Variant 9-95508271-C-T is Benign according to our data. Variant chr9-95508271-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 486165.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5 linkuse as main transcript	c.91G>A	p.Gly31Arg	missense_variant	1/24	ENST00000331920.11
PTCH1	NM_001083603.3 linkuse as main transcript	c.199-1672G>A		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11 linkuse as main transcript	c.91G>A	p.Gly31Arg	missense_variant	1/24	5	NM_000264.5	A2	Q13635-1
PTCH1	ENST00000437951.6 linkuse as main transcript	c.199-1672G>A		intron_variant		5	NM_001083603.3		Q13635-2

Frequencies

GnomAD3 genomes

AF:

0.0000396

AC:

AN:

151702

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000885

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000430

AC:

AN:

186222

Hom.:

AF XY:

0.0000288

AC XY:

AN XY:

104028

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000143

Gnomad NFE exome

AF:

0.0000605

Gnomad OTH exome

AF:

0.000212

GnomAD4 exome

AF:

0.000102

AC:

145

AN:

1418492

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

703154

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000154

GnomAD4 genome

AF:

0.0000396

AC:

AN:

151702

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74050

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000885

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ExAC

AF:

0.0000265

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Gorlin syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Benign

0.17

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.68

MutationAssessor

Benign

-1.4

MutationTaster

Benign

1.0

D;D;D;D;N

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

0.40

REVEL

Benign

0.17

Sift

Benign

0.39

Sift4G

Benign

0.60

Polyphen

0.0020

Vest4

0.23

MutPred

0.28

Gain of methylation at G31 (P = 0.0101);

MVP

0.22

MPC

1.6

ClinPred

0.12

GERP RS

1.2

Varity_R

0.060

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over